The invention relates to novel mixed inhibitors of the neprilysin and aminopeptidase N.
It is known that natural opioid peptides or enkephalins—(Tyr-Gly-Gly-Phe-Met or Tyr-Gly-Gly-Phe-Leu)—are primarily degraded by two zinc metallopeptidases, neprilysin (EC 3.4.24.11) which cleaves the Gly3-Phe4 bond (Nature 276 (1978) 523) and aminopeptidase N (EC 3.4.11.2) which cuts the Tyr1-Gly2 bond of these peptides (Eur. J. Pharmacol. 117 (1985) 233; review in Pharmacological Review., 1993, 45, 87-146). Mixed inhibitors of these two enzymes are known, by completely protecting endogenous enkephalins from enzymatic degradation, they reveal the pharmacological activities, in particular analgesic and antidepressant activities, of enkephalins. Mixed inhibitors, described in the prior art, of these two enzymatic activities are compounds with a hydroxamate function (FR 2 518 088 and FR 2 605 004), aminophosphinic compounds (FR 2 755 135 and FR 2 777 780) and amino acid derivatives (FR 2 651 229). The compounds divulged in these patent applications exhibit excellent in vitro and in vivo activity after administration by intracerebroventricular route; this was particularly demonstrated in the case of the hydroxamates (Eur. J. Pharmacol., 102, (1984), 525-528; Eur. J. Pharmacol., 165, (1989), 199-207; Eur. J. Pharmacol, 192, (1991), 253-262), for which significant activity also could be demonstrated after intravenous (IV) administration in a model of rat arthritis (Brain Research, 497, (1989), 94-101). In the case of aminophosphinic derivatives and amino acid derivatives, good in vivo activity was demonstrated after administration by IV route when the molecules studied were solubilized in a mixture of oil, ethanol and water (J. Med. Chem., 43, (2000), 1398-1408; J. Med. Chem., 44, (2001), 3523-3530; J. Pharm. Exp. Ther., 261, (1992), 181-190). However, even if one of the compounds belonging to the series of amino acid derivatives proved relatively water soluble (Pain, 73, (1997), 383-391), none the molecules previously divulged exhibits solubility in an aqueous phase and sufficient bioavailability to be administered by oral route and to provide advantageous analgesic responses to sufficiently low doses in animals to be adapted to man. Similarly, none the molecules previously cited allows intravenous administration since in animal tests they require solubilization in mixtures incompatible with administration by this route in man.
One of the objects of the invention is to provide novel water-soluble compounds capable of jointly inhibiting the two enzymatic activities responsible for the degradation of enkephalins and to manifest their pharmacological properties after dissolution in an aqueous solvent and intravenous, subcutaneous, percutaneous, intrathecal or intra-articular injection and by oral or nasal route.
It is generally understood that the hematoencephalic barrier is more easily crossed by hydrophobic and non-polar molecules. However, unexpectedly, the hydrophilic molecules that have been synthesized exhibit powerful responses in central tests indicating the existence of a good capacity to reach cerebral structures by several administration routes (except for the local route). Another object of the invention is to provide novel compounds that exhibit the properties of morphine substances, in particular analgesia, beneficial effects on behavior (reduction in the emotional component of pain and antidepressant responses) and peripheral effects (antidiarrheal, antitussive, anti-inflammatory) without their major disadvantages (tolerance, physical and psychological dependence, respiratory depression, constipation, nausea).
Moreover, inflammatory and neurogenic pain, whose peripheral component is significant, are reduced or even eliminated by the compounds according to the invention administered by oral route and thus without such compounds being constrained from reaching the central nervous system. This result, highly advantageous but unexpected, was formally demonstrated by the use of an antagonist incapable of entering the brain. This completely reduces all of the effects due to stimulation of cerebral opioid receptors by the compounds according to the invention, without altering the analgesics effects of the compounds on these types of pain, in particular neurogenic pain.
Most notably, the invention relates to compounds of following formula (I):H2N—CH(R1)—CH2—S—S—CH2—CH(R2)—CONH—R5 
wherein:    R1 represents:            a hydrocarbon chain, saturated or unsaturated, linear or branched, comprising from 1 to 6 carbon atoms, optionally substituted by:                    an OR, SR or S(O)R radical, wherein in each of these radicals R represents a hydrogen, a linear or branched hydrocarbon chain of 1 to 4 carbon atoms, a phenyl or benzyl radical,            a phenyl or benzyl radical,                        a phenyl or benzyl radical optionally substituted by:                    1 to 5 halogens, notably fluorine,            an OR, SR or S(O)R radical, wherein in each of these radicals R is defined as above,                        a methylene radical substituted by a 5- or 6-atom heterocycle, aromatic or saturated, having as a heteroatom an atom of nitrogen or sulfur, optionally oxidized in the form of N-oxide or S-oxide;            R2 represents:            a phenyl or benzyl radical, optionally substituted by:                    1 to 5 halogen atoms, notably fluorine,            an OR or SR radical, wherein in each of these radicals R is defined as above,            an amino group optionally mono- or di-substituted by an aliphatic, cyclic or linear group of 1 to 6 carbon atoms,            a 5- or 6-atom aromatic ring,                        a 5- or 6-atom aromatic heterocycle, the heteroatom being oxygen, nitrogen or sulfur,        a methylene group substituted by a 5- or 6-atom heterocycle, aromatic or saturated, the heteroatom being oxygen, nitrogen or sulfur, the nitrogen and sulfur atoms possibly being oxidized in the form of N-oxide or S-oxide.            R5 represents:    a) a CH(R3)—COOR4 radical wherein
R3 represents:                hydrogen,        an OH or OR group, with R as defined above,        a saturated hydrocarbon chain (alkyl), linear or branched, comprising from 1 to 6 carbon atoms, optionally substituted by an OR or SR radical, wherein in each of these radicals R is defined as above,        a phenyl or benzyl radical, optionally substituted by:                    1 to 5 halogens, notably fluorine,            an OR or SR radical, with R as defined above. and                        
OR4 represents                an OCH2COOR′ glycolate or OCH(CH3)COOR′ lactate radical, wherein in each of these radicals R′ represents                    a saturated hydrocarbon chain (alkyl) with 1 to 6 carbon atoms, linear or branched and optionally substituted by an alkoxy group at C1 to C3, preferably an alkyl group at C1-C4 optionally substituted by a methoxy group,            a cycloalkyl group at C5-C8, preferably a cycloalkyl group at C5-C6,            a phenyl, benzyl, heteroaryl, alkylheteroaryl group,                        an OCH(R″)O(CO)OR or OCH(R″)O(CO)R′ group, wherein in each of these radicals R′ is defined as above and R″ represents                    a hydrogen atom,            a C1-C6 alkyl chain, linear or branched, optionally substituted by a C1-C3 alkoxy group, preferably a C1-C4 alkyl group optionally substituted by a methoxy group,            a C5-C8 cycloalkyl group, preferably a C5-C6 cycloalkyl group,            a phenyl, benzyl, heteroaryl, alkylheteroaryl group,                        an OCH(CH2OCOR′)2 or OCH2—CH(OCOR′)—CH2OCOR′ triglyceride radical, wherein in each of these radicals R′ is defined as above,        a glycoside radical such as D-glucose, β-D-glucopyranose, α- or β-galactopyranose,        an OCH2CH2(SO2)CH3 sulfonate radical,        an OCH(CH2OH)2 radical;            b) a 5- or 6-link heterocycle comprising several heteroatoms selected from the group comprised of nitrogen, sulfur and oxygen, of which 2 atoms are nitrogen, said heterocycle possibly being substituted by a C1-C6 alkyl, phenyl or benzyl radical;
as well as additive salts of the aforesaid compounds (I) with pharmaceutically acceptable mineral or organic acids.
The invention also has as an object additive salts of compounds of formula (I), obtained with pharmacologically acceptable organic or mineral acids such as phosphates, hydrochloride, acetate, methanesulfonate, borate, lactate, fumarate, succinate, hemisuccinate, citrate, tartrate, hemitartrate, maleate, ascorbate, hemifumarate, hexanoate, heptanoate, hippurate, hydrocinnamate, phenylglyoxylate and nicotinate.
Within the framework of the present invention, the expression “hydrocarbon chains” designates alkanes, alkenes or alkynes. Notably, the expression “saturated hydrocarbon chains” designates alkyl radicals comprising from 1 to 6 carbon atoms (C1-C6) or from 1 to 4 carbon atoms (C1-C4), linear or branched. Examples of alkyl radicals comprising from 1 to 4 carbon atoms include methyl, ethyl, propyl, butyl, isopropyl, 1-methyl-ethyl, 1-methyl-propyl and 2-methyl-propyl radicals. Examples of alkyl radicals comprising from 1 to 6 carbon atoms further include pentyl, hexyl, 1-methyl-butyl, 1-methyl-pentyl, 2-methyl-butyl, 2-methyl-pentyl, 3-methyl-butyl, 3-methyl-pentyl, 4-methyl-pentyl or 1-ethyl-propyl, 1-ethyl-butyl and 2-ethyl-butyl radicals. The expression “unsaturated hydrocarbon chains” designates alkenyl radicals (at least one double bond), for example vinyl, allyl or similar, or alkynyl (at least one triple bond) comprising from 2 to 6 atoms of carbon, or 2 to 4 carbon atoms, linear or branched.
The term “halogen” used herein designates chlorine, bromine, iodine or fluorine.
As non-limiting example of heterocyclic cores with 5 or 6 atoms, aromatic or saturated, having as a heteroatom an atom of nitrogen or sulfur, the following radicals can be cited: thienyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, thiadiazolyle, the nitrogen and sulfur atoms optionally being oxidized in the form of N-oxide or S-oxide.
As non-limiting example of heterocyclic cores with 5 or 6 atoms, aromatic or saturated, having as a heteroatom an atom of oxygen, the following radicals can be cited: furyl, pyranyl, isoxazolyl, morpholinyl, furazanyl, oxazolyl, oxazolidinyl and oxazolinyl.
Radical R1 advantageously represents an alkyl radical having from 1 to 4 atoms of carbon, optionally substituted by an OR, SR or S(O)R radical, wherein in each of these radicals R is defined as above. R1 represents even more advantageously an alkyl radical having from 1 to 4 carbon atoms substituted by a SR radical, with R defined as above, notably with R representing a saturated hydrocarbon chain, linear or branched, with 1 to 4 atoms of carbon.
Radical R2 advantageously represents:                a benzyl or phenyl radical,        a methylene radical substituted by a 5- or 6-atom heterocycle, aromatic or saturated, having as a heteroatom an atom of nitrogen or sulfur, optionally oxidized in the form of N-oxide or S-oxide.        
Notably, radical R2 represents a benzyl radical or a methylene radical substituted by a 5- or 6-atom heterocycle, aromatic or saturated, having as a heteroatom a sulfur or nitrogen atom, optionally oxidized in the form of N-oxide or S-oxide, even more advantageously a benzyl radical or a methylene radical substituted by a thiophenyl radical (thienyl).
Radical R5 is a radical that increases the hydrophilic character of the whole molecule, which normally is a rather hydrophobic molecule.
According to a first embodiment of the invention, radical R5 represents a CH(R3)—COOR4 radical.
In this first embodiment, radical R3 advantageously represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms, even more advantageously 1 to 4 carbon atoms, optionally substituted by an OR or SR radical, wherein in each of these radicals R is defined as above. Radical R3 even more advantageously represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms, even more advantageously 1 to 4 carbon atoms, substituted by an OH or SH radical.
Radical OR4 advantageously represents:                an OCH2COOR′ glycolate radical, with R′ as defined above (notably R′ represents a C1-C4 alkyl group optionally substituted by a methoxy group or a C5-C6 cycloalkyl group),        an OCH(R″)O(CO)OR′ or OCH(R″)O(CO)R′ radical, with R′ and R″ as defined above (notably R′ and/or R″ represent a C1-C4 alkyl group optionally substituted by a methoxy group or a C5-C6 cycloalkyl group or R″ represents a hydrogen atom),        an OCH(CH2OCOR′)2 or OCH2—CH(OCOR′)—CH2OCOR′ triglyceride radical, wherein in each of these radicals R′ is defined as above,        a glycoside radical such as D-glucose,        an OCH2CH2(SO2)CH3 sulfonate radical,        an OCH(CH2OH)2 radical.        
Notably, radical OR4 represents an OCH(R″)O(CO)OR′ or OCH(R″)O(CO)R′ group, the R′ radical representing a C1-C4 alkyl chain (notably an ethyl radical) and the R″ radical representing a methyl, CH(CH3)2, cyclohexyl or phenyl radical.
According to a second embodiment of the invention, radical R5 represents a heterocycle, of 5 or 6 links, comprising several heteroatoms, selected among the group comprising nitrogen, sulfur and oxygen, of which 2 atoms are nitrogen, said heterocycle possibly substituted by a C1-C6 alkyl radical or a phenyl or benzyl radical.
In said second embodiment, the heterocycle is advantageously a 5-link heterocycle comprising 2 nitrogen atoms, optionally substituted by a C1-C4 alkyl chain, notably 2-ethyl-1,3,4-thiadiazole.
The invention notably relates to the following compounds:    1-(2-(1-(2,3-diacetoxypropoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine,    1-(2-(1-(2-methanesulfonylethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine,    1-(2-(1-(1-ethoxycarbonyloxyethoxycarbonyl))-ethylcarbamoyl)-3-thiophen-3-yl-propyldisulfanylmethyl)-3-methylsulfanylpropyl-amine,    1-(2-(1-ethoxycarbonylmethyloxycarbonylethylcarbamoyl)-3-thiophen-3-yl-propyldi sulfanylmethyl)-3-methylsulfanylpropyl-amine,    1-(2-(1-(1-ethoxycarbonyloxyethoxycarbonyl)-2-hydroxypropylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine,    1-(2-(1-(2-acetoxy-1-acetoxymethylethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine,    1-(2-(1-(2-hydroxy-1-hydroxymethylethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-ylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine,    1-(2-(1-(3,4,5,6-tetrahydroxytetrahydropyran-2-ylmethoxycarbonyl)-ethylcarbamoyl)-3-thiophen-3-yl-propyldisulfanylmethyl)-3-methylsulfanylpropyl-amine,    1-(2-(1-(1-ethoxycarbonyloxy-ethoxycarbonyl)-2-hydroxypropylcarbamoyl)-3-phenylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine,    1-(2-(1-(2-acetoxy-1-acetoxymethyl-ethoxycarbonyl)-2-hydroxypropylcarbamoyl)-3-phenylpropyldisulfanylmethyl)-3-methylsulfanylpropyl-amine,    1-(2-((1-ethoxycarbonyloxy-ethoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanylpropyl-amine,    3-(2-amino-4-methylsulfanyl-butyldisulfanyl)-2-benzyl-N-(5-ethyl-(1,3,4)-thiadiazol-2-yl)-propionamide,    1-(2-((1-ethoxycarbonyloxy-2-methyl-propoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine,    1-(2-((cyclohexyl-ethoxycarbonyloxy-methoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine,    1-(2-((ethoxycarbonyloxy-phenyl-methoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine,    3-methylsulfanyl-1-(3-phenyl-2-((1-propionyloxy-ethoxycarbonylmethyl)-carbamoyl)-propyldisulfanylmethyl)-propyl-amine,    1-(2-((2-methyl-1-propionyloxy-propoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine,    1-(2-((cyclohexyl-propionyloxy-methoxycarbonylmethyl)-carbamoyl)-3-phenyl-propyldisulfanylmethyl)-3-methylsulfanyl-propyl-amine,    3-methylsulfanyl-1-(3-phenyl-2-((phenyl-propionyloxy-methoxycarbonylmethyl)-carbamoyl)-propyldisulfanylmethyl)-propyl-amine.
The compounds of formula (I) potentially have from 2 to 9 centers of asymmetry. Radicals R1, R2 and R3 will be introduced in such a way as to obtain optically pure chains corresponding to stereochemistry recognized by enzymatic activities. Radicals R4 optionally contain an unresolved center of asymmetry.
The compounds of formula (I) are obtained:
1) by condensation of a protected beta-aminothiol on the amino function by a t-butyloxycarbonyl (Boc) group (II) with a mercaptoalcanoic acid (III) by means of methoxycarbonylsulfonyl chloride in solution in THF (tetrahydrofuran), leading to IV.
Boc beta-aminothiol II is prepared from the corresponding commercial Boc amino acid of absolute configuration S with retention of configuration according to a method well-known by those skilled in the art (J. Med. Chem., 35, (1992) 1259).
The mercaptoalcanoic acid III is obtained from the corresponding methyl malonate monoester V, which, according to a method well-known by those skilled in the art (Ber., 57, (1924), 1116) is transformed into acrylate VI.

The addition of thioacetic acid to acrylate VI leads to racemic derivative VII (Biochemistry, 16, (1977), 5484). Resolution by alpha-chymotrypsin isolates the optically pure acetylthioacide VIII (Bioorg. Med. Chem. Let, 3, (1993), 2681). Alkaline hydrolysis of the thioester leads to compound III.
2) The compounds of formula (I), wherein radical R5 represents a CH(R3)—COOR4 radical, can be obtained by the following synthetic pathways.
2.1) Dissymmetrical disulfide IV is coupled, under conventional peptide coupling conditions, with aminoester IX, leading to the protected inhibiter X.

According to an alternative method, compounds X can be obtained by condensation, by means of methoxycarbonyl sulfenyl chloride, of Boc-β-aminothiol II with a mercaptoacylaminoester of formula XI.
Mercaptoacyl aminoester XI is prepared from compound III. It is oxidized by an ethanolic iodine solution into disulfide XII. Compound XII is coupled under conventional peptide coupling conditions with aminoester IX, leading to XIII. Treatment of XIII with a reducing agent such as the mixture 3 N Zn+HCl, releases compound XI.

The N-terminal Boc group of X is cut by the action of formic acid, releasing XIV. The counter-ion of XIV is changed quantitatively by treatment with one equivalent of 0.1 M NaHCO3, extraction in an organic medium (EtOAc) of the compound possessing a free amino function, then addition of one equivalent of the organic acid or mineral chosen to lead to I.
2.2) Aminoester IX is obtained by condensation of Boc amino acid XII with alcohol R4OH, then deprotection by trifluoroacetic acid (TFA) and neutralization by soda. If alcohol R4OH is a primary alcohol, coupling with XII is carried out under conventional conditions (1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole hydrate (HOBt) or activated ester). If alcohol R4OH is a secondary alcohol, condensation is achieved via a Mitsunobu reaction (Synthesis (1981) 1-28), using the mixture diethyl azodicarboxylate/triphenyl phosphine (DEAD/PPhe3).

Alcohols R4OH are in most cases commercial compounds. When R4OH is an alcohol leading to an ester “cascade,” it is synthesized from methods described in the literature.
2a) Compounds of formula (I), wherein radical R5 represents a heterocycle radical such as defined above, can be obtained by the following synthetic pathways.
2.a.1)

Dissymmetrical disulfide IV is coupled under conventional peptide coupling conditions with amino heterocycle XV to lead to XVI. Deprotection of the Boc group is carried out as above leading to derivative XVII.

Amino heterocycle XV is synthesized according to methods described in the literature.
For example, 2-amino-5-ethyl-(1,3,4)thiadiazole XVa is obtained as described (Takatori et al., Yakugaku Zasshi 79,1959,913) by condensation of thiosemicarbazide XVIII and propionyl chloride XIX.

According to an alternative method, compounds of formula (1), wherein radical R5 represents a heterocycle, can be obtained by condensation of heterocycle XV on compound XII, leading to XX. After cutting the disulfide bridge, as previously described, the compound obtained XXI is condensed on II to lead to XVI.

The invention also has as an object pharmaceutical compositions comprising as active ingredient at least one compound of general formula (I) or a salt of same or salt hydrates of same in combination with one or more pharmaceutically acceptable inert carriers or other vehicles. These compounds exhibit the properties of morphine substances, notably analgesia, including peripheral components (inflammatory, neurogenic), beneficial effects on behavior, notably in the case of depression and/or anxiety, without exhibiting their major disadvantages (tolerance, dependence, respiratory depression, constipation).
Thus, contrary to exogenous opioid agonists that interact with delta receptors, the inventive mixed inhibitors have antidepressant effects without the risk of triggering epileptiform activity or convulsions, and they are fast acting (Baamonde A. et al., 1992, Jutkiewicz E. M. et al., 2005). These compounds can pass the blood-brain barrier. The principal application of the compounds according to the invention is thus in the field of analgesia, antidepressants and anxiolytics.
The inventive pharmaceutical compositions can be, as example, compositions administered by oral, nasal (administration by aerosol), sublingual (administration by perlingual diffusion), rectal, parenteral, intravenous and percutaneous route. Examples of compositions administered by oral route include tablets, gelatin capsules, granules, microspheres, powders and oral solutions or suspensions. Radical R5 confers sufficient hydrophily on the compounds according to the invention, which are thus soluble in water and hydrophilic solvents in the presence of absence of various surfactants. Notably, they are soluble in alcohol/polysorbate/water solvents, notably ethanol/Tween®/water and mannitol/water or with the assistance of cyclodextrins suitable for administration in man, which are frequently used for administration by intravenous route. The compositions according to the invention can thus be administered by intravenous route. They can also be administered by oral or nasal route, notably via an aerosol or by perlingual diffusion or within a suitable galenic preparation (microemulsions). Similarly, these compositions can be used for transdermal administration. These compositions can be used notably as major analgesics, powerful analgesics for inflammatory and neurogenic pain, and as antidepressants.
It is very advantageous that the compositions according to the invention can be administered either in the form of aerosols (microemulsions) by oral or nasal route or by intravenous route. These administration routes thus allow administration of the inventive composition by a non-digestive route. This is particularly advantageous when the composition comprises complementary compounds, which can exhibit undesired effects on the digestive system (notably the intestine), such as, for example, of cannabinoid derivatives. This also increases the cerebral bioavailability of compounds or combinations.
Another object of the invention is the use as a drug of compounds as defined above or obtained by a method as defined above.
Surprisingly, it was also noted that the combination of the novel compounds according to the present invention with cannabinoid derivatives leads to even stronger analgesic effects (superior to the sum of each effect observed for each compound, i.e., for the compounds according to the invention or the cannabinoid derivatives).
Until 1954, cannabis was regarded as a medicinal plant exhibiting multiple properties: analgesic, antispasmodic, anticonvulsive, anti-inflammatory, anti-vomitive, bronchodilator, vasodilator, relaxant and soporific. Recently, anti-proliferative and anti-neurodegenerative properties have been demonstrated.
Several harmful effects of cannabis, generally related to overdose, have been described: anxiety attacks for depressed patients and hallucinations when the product is consumed in drinks (tea) or food (cakes).
The effects of cannabis are explained by its action on cannabinoid receptors. These receptors are present in many cerebral structures and an endogenous molecule naturally related to it, anandamide, has been identified.
Two types of receptors have been characterized: CB1 receptors found in both the central nervous system and the periphery and CB2 receptors which are primarily peripheral. CB1 receptors appear involved in modulating neuronal release of excitory or inhibitory neurotransmitters in the brain. The role of CB2 receptors is less clear, but it seems that they intervene in the modulation of the immune system.
The endogenous molecules related to CB1 and CB2 receptors, called “endocannabinoids,” such as anandamide, interact with cannabinoid receptors in the brain and in the periphery by inducing various pharmacologic effects.
The most abundant psychotropic compound present in cannabis (Cannabis sativa) is Δ9 tetrahydrocannabinol (Δ9 THC).
Δ9 THC induces numerous pharmacological responses, such as analgesia, hypothermia, reduced locomotor activity and a loss of alertness and attention due to interactions with brain CB1 receptors. Some of these properties have advantageous therapeutic applications for the treatment of pain and glaucoma, as well as to attenuate nausea and to stimulate the appetite of patients treated with antitumor and antiviral compounds that have severe side effects. Δ9 THC, and more generally CB1 receptor agonists, is also able to reduce painful effects associated with multiple sclerosis while reducing the progress of the disease. Nevertheless, this led to the development of SATIVEX, which is a preparation directly arising from the plant (Cannabis sativa) and which contains a mixture in equal parts of Δ9 THC and cannabidiol (another substance present in the plant). This preparation is currently at the end of clinical testing. However, the doses administered by orobuccal route are high and side effects have been observed (Current Opinion in Investigational Drugs 2004, 5, 748).
Another characteristic of the endogenous endocannabinoid (anandamide) system relates to the mode of synthesis and secretion of this specific neurotransmitter. Formed by enzymatic route from organelle membrane phospholipids, anandamide is secreted by a transporter from a post-synaptic neuron to interact with CB1 receptors located on a presynaptic terminal (retrograde neurotransmission) (Piomelli et al., TIS, 2000, 21, 218-224).
However, several behavioral effects, such as a loss of alertness and attention, sedation, ataxia, vision trouble, tachycardia, hypothermia and behavioral disturbances such as hallucinations, anxiety, panic attacks and memory problems, produced by chronic exposure to natural or synthetic cannabinoids, limit their clinical use (reviewed in E. A. Carlini, The good and the bad effects of (−)trans-delta-9-tetrahydrocannabinol Δ9THC on humans, Toxicon, 2004, 44, 461-467). Moreover, in man, the analgesic effects of Δ9 THC are obtained at high doses near to the amounts that cause the adverse effects mentioned above (Campbell F. A. et al., Are cannabinoids an effective and safe treatment option in management of pain? A quantitative systemic review, Br. Med. J., 2001, 323, 12-16).
Surprisingly, it has been noted that the co-administration (simultaneous or over time) of low doses of cannabinoid derivatives (notably Δ9 THC) potentiates the analgesic effect and the antidepressant effect of the derivatives according to the invention (formula (I)) without significantly inducing harmful effects of said cannabinoids, which by IV route appear beginning at 4-5 mg/kg (sedation).
In the present invention, the expression “very low cannabinoid concentrations” means cannabinoid concentrations below those inducing said undesirable side effects.
In the present invention, the expression “cannabinoid” means Δ9 THC, synthetic CB1 receptor agonists or anandamide degradation inhibitors. The cannabinoids introduced into the compositions according to the invention are preferably Δ9 THC.
The invention also has as an object a pharmaceutical composition comprising at least one compound of formula (I) as defined above, at least one cannabinoid derivative, notably Δ9 THC, or a protector of its metabolism (reviewed in Piomelli et al., TIPS, 2000), and a pharmaceutically suitable excipient, in particular an excipient suitable for administration by oral, nasal, intravenous or transcutaneous route.
The invention also relates to the use of at least one cannabinoid derivative, in particular Δ9 THC, in a pharmaceutical composition to potentiate the analgesic and/or antidepressant effect of compounds of formula (I) as defined above.
The invention also relates to the use of a combination of at least one compound of formula (I) as defined above and of at least one cannabinoid derivative, in particular Δ9 THC, for preparing a drug intended for the treatment of depression and of pain.
Another object of the invention is a pharmaceutical composition comprising:
i) at least one compound of formula (I) as defined above,
ii) at least one cannabinoid derivative as combination products for simultaneous, separate or staggered use.
Similarly, the invention also has as an object the use of a pharmaceutical composition comprising
i) at least one compound of formula (I) as defined above,
ii) at least one cannabinoid derivative as combination products for simultaneous, separate or staggered use, for manufacture of a drug to treat depression and pain.
Within the framework of the present invention, the term “pain” means the various types of pain, such as acute pain, inflammatory pain and neurogenic pain, including pain associated with multiple sclerosis. The compounds according to the invention, optionally in combination with a cannabinoid derivative, are also suitable for the treatment of glaucoma.
The invention also has as an object the combination of the novel compounds according to the invention with morphine or a derivative of same. Indeed, morphine is also able to potentiate the analgesic effect induced by the compounds according to the invention.
Thus, the invention has as an object a pharmaceutical composition comprising at least one compound of formula (I) as defined above, of morphine or a derivative of same and a pharmaceutically suitable excipient, notably an excipient suitable for administration by oral, nasal, intravenous or transcutaneous route. The composition can in addition comprise at least one cannabinoid derivative, notably Δ9 THC, or a protector of its metabolism.
The invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined above and in addition Gaba derivatives. The Gaba derivative is preferably Gabapentin or pregabalin. The addition of a Gaba derivative, as demonstrated with Gabapentin, can potentiate the effects induced by the compounds of formula (I). The inventors surprisingly show that Gaba derivatives (in particular Gabapentin) and compounds of formula (I) have synergistic analgesic effects. In particular, administering the two drugs (i.e. a—the compound of formula (I) and b—the Gaba derivative) at a dose (the dose is the weight of drug administered par kilo of the subject to be treated, it is expressed by mg/kg), at which each drug alone does not show analgesic effect, surprisingly was effective. The analgesic effects induced by both drugs are strongly potentiated in such a way that doses of both drugs ineffective if administered alone are effective when associated.
The dose ratio of compound of formula (I): Gaba derivative (Gabapentin) is preferably between 1:2 and 2:1. In particular, the dose ratio of compound of formula (I): Gaba derivative (Gabapentin) is 2:1.
Thus, the invention has as an object a method for treating depression and particularly pain comprising the administration of an effective amount of a synergistic combination of at least one compound of formula (I) as defined above and a Gaba derivative, preferably Gabapentin or pregabalin, to a patient in need thereof.
This composition can be used as a drug, notably in the treatment of depression and pain. The various compounds can be used as combination products in a simultaneous, separate or staggered fashion.
It is the good aqueous solubility of the compounds according to the invention of formula I that greatly facilitates the constitution of the preparation (microemulsions, in solution in the presence of surfactants, etc.) suitable for therapeutic use by intravenous, nasal, pulmonary (aerosol) or transcutaneous routes.
The effective dose of the inventive compound varies according to a number of parameters, such as, for example, the administration route chosen; the patient's weight, age and sex; the stage of the pathology to be treated; and the patient's sensitivity. Consequently, optimal dosing will be determined, according to the parameters considered to be relevant, by the relevant specialist.